Molecular transport in living systems regulates numerous processes underlying biological function.
Although many cellular components exhibit anomalous diffusion, only recently has the subdiffusive
motion been associated with nonergodic behavior. These findings have stimulated new questions for their
implications in statistical mechanics and cell biology. Is nonergodicity a common strategy shared by living
systems? Which physical mechanisms generate it? What are its implications for biological function? Here,
we use single-particle tracking to demonstrate that the motion of dendritic cell-specific intercellular
adhesion molecule 3-grabbing nonintegrin (DC-SIGN), a receptor with unique pathogen-recognition
capabilities, reveals nonergodic subdiffusion on living-cell membranes In contrast to previous studies, this
behavior is incompatible with transient immobilization, and, therefore, it cannot be interpreted according to
continuous-time random-walk theory. We show that the receptor undergoes changes of diffusivity,
consistent with the current view of the cell membrane as a highly dynamic and diverse environment.
Simulations based on a model of an ordinary random walk in complex media quantitatively reproduce all
our observations, pointing toward diffusion heterogeneity as the cause of DC-SIGN behavior. By studying
different receptor mutants, we further correlate receptor motion to its molecular structure, thus establishing
a strong link between nonergodicity and biological function. These results underscore the role of disorder
in cell membranes and its connection with function regulation. Because of its generality, our approach
offers a framework to interpret anomalous transport in other complex media where dynamic heterogeneity
might play a major role, such as those found, e.g., in soft condensed matter, geology, and ecology.